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CD6 knockout HER2 chimeric antigen receptor (CAR) T cells are an experimental adoptive cellular therapy designed to treat solid tumors, with a primary focus on glioblastoma (GBM). These T cells are engineered to express a chimeric antigen receptor targeting the Human Epidermal Growth Factor Receptor 2 (HER2), typically utilizing a CD28ζ signaling domain. To investigate the role of the CD6 adhesion molecule in CAR T cell functionality and metabolic fitness, the CD6 gene is deleted using CRISPR-Cas9 technology. CD6 is a signal modulator that shares components of both activating and inhibitory signalosomes; its removal in this construct was found to impair effector functions in preclinical models, leading researchers at Baylor College of Medicine to explore the overexpression of specific CD6 isoforms (such as CD6F) as a superior alternative to complete knockout. The knockout version serves as a critical tool in understanding how to decouple tonic signaling from antigen-driven activation to improve the durability of CAR T cell therapies.
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